You are here:
TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS
Citation:
HU, W., D. J. DIX, C. S. LAU, R. J. KAVLOCK, E. AYANOGLU, AND R. BRENNAN. TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Description:
Toxicogenomic analysis of five environmental contaminants was performed to investigate the ability of genomics to categorize chemicals and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole and triadimefon) and two perfluorinated compounds (perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS)) were administered daily via oral gavage for 1, 3, and 5 consecutive days to male Sprague-Dawley rats at doses of 300, 300, 175, 20, and 10 mg/kg, respectively. Clinical observations, clinical chemistry, hematology and liver histopathology were measured at all time points. Expression profiling of livers from 3 rats per treatment group at all time points was performed on CodeLink RU1 microarrays. Data were analyzed in context with DrugMatrix, a large toxicogenomic database with expression data on over 630 compounds. All compounds resulted in similar liver histopathology, but gene expression analysis segregated the compounds into two distinct classes. Myclobutanil, propiconazole and triadimefon were similar to other azole antifungals in the database, with PXR associated up-regulation of xenobiotic metabolism genes and the induction of oxidative stress and cell cycle genes. In contrast, PFOA and PFOS exhibited PPAR agonist effects, with down-regulation of cholesterol biosynthesis genes matched by decreased serum cholesterol levels in vivo. PFOA and PFOS gene expression patterns also suggested estrogenicity, possibly through up-regulation of aromatase. Thyroid hormone depletion by PFOA and PFOS in vivo was consistent with perturbation of thyroid hormone metabolism genes. The concordance of in vivo observations and gene expression findings shows the potential for gene expression analysis to accurately categorize chemicals and identify modes of toxic action. This abstract of a proposed presentation does not necessarily reflect EPA policy.